* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download C:\Documents and Settings\Reb...uhi.default\Cache\0F1E60D5d01
Antihypertensive drug wikipedia , lookup
History of invasive and interventional cardiology wikipedia , lookup
Cardiac contractility modulation wikipedia , lookup
Heart failure wikipedia , lookup
Cardiac surgery wikipedia , lookup
Mitral insufficiency wikipedia , lookup
Electrocardiography wikipedia , lookup
Remote ischemic conditioning wikipedia , lookup
Jatene procedure wikipedia , lookup
Hypertrophic cardiomyopathy wikipedia , lookup
Quantium Medical Cardiac Output wikipedia , lookup
Coronary artery disease wikipedia , lookup
Management of acute coronary syndrome wikipedia , lookup
Heart arrhythmia wikipedia , lookup
Ventricular fibrillation wikipedia , lookup
Arrhythmogenic right ventricular dysplasia wikipedia , lookup
Kevin Kit Parker, James A. Lavelle, L. Katherine Taylor, Zifa Wang and David E. Hansen J Appl Physiol 97:377-383, 2004. doi:10.1152/japplphysiol.01235.2001 You might find this additional information useful... This article cites 58 articles, 30 of which you can access free at: http://jap.physiology.org/cgi/content/full/97/1/377#BIBL This article has been cited by 3 other HighWire hosted articles: The effect of streptomycin on stretch-induced electrophysiological changes of isolated acute myocardial infarcted hearts in rats F. Lu, C. Jun-xian, X. Rong-sheng, L. Jia, H. Ying, Z. Li-qun and D. Ying-nan Europace, August 1, 2007; 9 (8): 578-584. [Abstract] [Full Text] [PDF] Acute volume overload elevates T-wave alternans magnitude S. M. Narayan, D. D. Drinan, R. P. Lackey and C. F. Edman J Appl Physiol, April 1, 2007; 102 (4): 1462-1468. [Abstract] [Full Text] [PDF] Medline items on this article's topics can be found at http://highwire.stanford.edu/lists/artbytopic.dtl on the following topics: Physiology .. Cardiac Muscle Pharmacology .. Heart Diseases (Drug Development) Physiology .. Coronary Arteries Physiology .. Action Potential Medicine .. Arrhythmia Medicine .. Ischemia Updated information and services including high-resolution figures, can be found at: http://jap.physiology.org/cgi/content/full/97/1/377 Additional material and information about Journal of Applied Physiology can be found at: http://www.the-aps.org/publications/jappl This information is current as of January 5, 2009 . Journal of Applied Physiology publishes original papers that deal with diverse areas of research in applied physiology, especially those papers emphasizing adaptive and integrative mechanisms. It is published 12 times a year (monthly) by the American Physiological Society, 9650 Rockville Pike, Bethesda MD 20814-3991. Copyright © 2005 by the American Physiological Society. ISSN: 8750-7587, ESSN: 1522-1601. Visit our website at http://www.the-aps.org/. Downloaded from jap.physiology.org on January 5, 2009 Intracoronary infusion of Gd3+ into ischemic region does not suppress phase Ib ventricular arrhythmias after coronary occlusion in swine J. A. Barrabes, D. Garcia-Dorado, L. Agullo, A. Rodriguez-Sinovas, F. Padilla, L. Trobo and J. Soler-Soler Am J Physiol Heart Circ Physiol, June 1, 2006; 290 (6): H2344-H2350. [Abstract] [Full Text] [PDF] J Appl Physiol 97: 377–383, 2004; 10.1152/japplphysiol.01235.2001. TRANSLATIONAL PHYSIOLOGY Stretch-induced ventricular arrhythmias during acute ischemia and reperfusion Kevin Kit Parker,1 James A. Lavelle,2 L. Katherine Taylor,2 Zifa Wang,2 and David E. Hansen2 1 Living State Physics Group, Department of Physics and Astronomy, Vanderbilt University, and 2Division of Cardiology, Department of Internal Medicine, Vanderbilt University School of Medicine, Nashville, Tennesse 37232 Submitted 14 December 2001; accepted in final form 22 January 2004 VENTRICULAR ARRHYTHMIAS ACCOMPANYING an arrest of myocardial perfusion are the primary cause of death in the majority of fatalities associated with myocardial infarction and are a major provocation of sudden cardiac death (50). The role of acute myocardial ischemia in fatal arrhythmias has been studied (10, 38 – 40, 44) and attributed to the alteration in electrical properties of ventricular tissue, affecting excitability and conduction of the action potential (23, 46, 63). These interruptions in normal electrical function of the myocyte are the result of altered membrane ionic currents and their diastolic concentrations in both the intra- and extracellular spaces (43, 63). Arrhythmias associated with ischemia are generally classified as phase I (during the first 30 min), phase II (between 5 and 72 h), and phase III (chronic stage after infarct). Phase I arrhythmias are further subdivided into Ia and Ib, where Ia arrhythmias occur during the first 10 min of ischemia and are due to both reentrant and triggered mechanisms and Ib arrhythmias occur between 20 and 30 min of ischemia and are of reentrant means. Reperfusion-induced arrhythmias after ischemic episodes are attributed primarily to triggered mechanisms. Triggered arrhythmias are characterized by an external stimulus, primarily classified as early afterdepolarizations or afterdepolarizations. In studies directed toward understanding the role of mechanoelectrical coupling in arrhythmogenesis, early afterdepolarizations have been associated with increased stretch conductance in computer simulations (43) and in mechanically induced ectopic beats in experimental studies (13). Myocardial stretch during the action potential has been observed to alter the action potential duration (19, 20, 22, 24), whereas transient diastolic stretch has been shown to result in depolarization (36), often sufficient to elicit an action potential (13, 24). Mechanical stretch has been demonstrated to generate atrial and ventricular arrhythmias (14, 17, 41, 51). Regional inhomogeneities in contractility and mechanical restitution may serve as foci for stretch-induced arrhythmias (SIAs). These inhomogeneities can be attributed to localized ischemia (12, 42) or hypertrophy localized to various regions on the ventricular free wall and septum (11). Such inhomogeneities will result in abnormal distributions of strain in the ventricular wall. The presence of abnormalities in left ventricular (LV) wall motion has been correlated with the incidence of cardiac arrhythmias (6, 31) and sudden cardiac death among patients with coronary artery disease (6). We hypothesize that this dyskinesis will perturb membrane conductivities with the potential to display altered kinetics during mechanical perturbation (15, 32, 58), potentiating an increase in SIAs. We tested the hypothesis that regional ischemia is more conducive than global ischemia to ventricular SIAs and from these results developed an ischemic heart model to test our hypothesis that mechanical stretch may underlie phase Ia and reperfusion ventricular arrhythmias. Furthermore, we hypothesized that regionally ischemic hearts would not be as susceptible to SIAs during phase Ib, when reentrant arrhythmogenesis is observed. We found that the probability of eliciting an SIA is higher during regional ischemia than during global ischemia even when contractile capabilities are comparable. Furthermore, we observed that the incidence of SIAs throughout 20 min of regional ischemia and 30 min of reperfusion matched previously reported profiles for triggered arrhythmias. In the Address for reprint requests and other correspondence: K. K. Parker, Div. of Engineering and Applied Sciences, Harvard University, 29 Oxford St., 322 Pierce Hall, Cambridge, MA 02138 (E-mail: [email protected]). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. ventricular; Langendorf; myocardial infarction; mechanoelectric signaling http://www. jap.org 8750-7587/04 $5.00 Copyright © 2004 the American Physiological Society 377 Downloaded from jap.physiology.org on January 5, 2009 Parker, Kevin Kit, James A. Lavelle, L. Katherine Taylor, Zifa Wang, and David E. Hansen. Stretch-induced ventricular arrhythmias during acute ischemia and reperfusion. J Appl Physiol 97: 377–383, 2004; 10.1152/japplphysiol.01235.2001.—Mechanical stretch has been demonstrated to have electrophysiological effects on cardiac muscle, including alteration of the probability of excitation, alteration of the action potential waveform, and stretch-induced arrhythmia (SIA). We demonstrate that regional ventricular ischemia due to coronary artery occlusion increases arrhythmogenic effects of transient diastolic stretch, whereas globally ischemic hearts showed no such increase. We tested our hypothesis that, during phase Ia ischemia, regionally ischemic hearts may be more susceptible to triggered arrhythmogenesis due to transient diastolic stretch. During the first 20 min of regional ischemia, the probability of eliciting a ventricular SIA (PSIA) by transient diastolic stretch increased significantly. However, after 30 min, PSIA decreased to a value comparable with baseline measurements, as expected during phase Ib, where most ventricular arrhythmias are of reentrant mechanisms. We also suggest that mechanoelectrical coupling may contribute to the nonreentrant mechanisms underlying reperfusion-induced arrhythmia. When coronary artery occlusion was relieved after 30 min of ischemia, we observed an increase in PSIA and the maintenance of this elevated level throughout 20 min of reperfusion. We conclude that mechanoelectrical coupling may underlie triggered arrhythmogenesis during phase 1a ischemia and reperfusion. 378 MECHANOARRHYTHMIAS DURING ISCHEMIA AND REPERFUSION phase Ib time period during which reentrant mechanisms are exclusively reported (38), our results show a decreased vulnerability to mechanically triggered ventricular arrhythmias. METHODS J Appl Physiol • VOL RESULTS Figure 1 shows examples of ventricular SIAs. Rapid change in LV volume may induce ventricular tachycardia (Fig. 1A). We often observe nonsustained ventricular tachycardia in our experimental preparation. When the stretch trigger is of sufficient magnitude and velocity, ventricular fibrillation can occur as depicted in Fig. 1B. In the present study protocol, high grades of ventricular ectopy were intentionally avoided when stretching, so as to prevent unnecessary degradation of the heart during the long experiments. A single or pair of premature ventricular contractions was typically elicited by a transient ventricular stretch that resulted in intraventricular pressures of ⬃80 mmHg, as previously reported (35). Arrhythmogenic mechanoelectrical coupling during regional and global ischemia. In chronically ischemic hearts, the incidence of arrhythmias accompanies the deterioration in mechanical function. However, in acute ischemia, we hypothesized that this would not always be the case. Recent theoretical calculations (25, 45) indicate that the inhomogeneity in contractility in the vicinity of the infarct would facilitate the development of localized regions of stretch that might serve as mechanoarrhythmogenic foci. This is in contrast to the globally ischemic heart, whose contractility is reduced in a relatively uniform manner. In Fig. 2A, we show Pmax, an indicator of ventricular contractility, and Ped, a measure of ventricular compliance, as a function of time for ischemic and mock ischemic hearts during ischemia and reperfusion. During 5 min of regional no-flow ischemia, a statistically significant decrease in Pmax is observed (P ⫽ 0.002). A statistically significant decrease in Pmax is also observed among hearts with 5 min of low-flow, global ischemia (P ⫽ 0.014). No statistically significant decrease in Pmax or Ped was observed for control hearts. After 5 min of their respective ischemic conditions, hearts of both modalities showed similar contractility, as indicated by mean Pmax values. Figure 2B depicts the observed changes in PSIA from preischemic to ischemic values. For mock ischemic and globally ischemic hearts, no statistically significant change was seen in PSIA over 5 min. Regionally ischemic hearts showed an increase in PSIA (P ⫽ 0.010) consistent with our hypothesis. That the overall contractility of both global and regionally ischemic hearts was comparable while regionally ischemic hearts were more susceptible to SIAs suggests that metabolically induced contractile dysfunction alone is not necessarily mechanoarrhythmogenic. The data indicate that an inhomogeneity may facilitate mechanical arrhythmogenesis and that common indicators of contractility may not elucidate the complex mechanical dysfunction underlying arrhythmogenic mechanoelectrical signaling. Arrhythmogenic mechanoelectrical coupling during regional ischemia and reperfusion. We then asked whether the PSIA profile during acute ischemia and reperfusion would appear similar to the arrhythmogenesis previously reported 97 • JULY 2004 • www.jap.org Downloaded from jap.physiology.org on January 5, 2009 Langendorf-perfused heart. The Langendorf perfusion system and stretch protocols have been previously reported (35). Briefly, hearts were harvested from male New Zealand White rabbits that were anesthetized with pentobarbital sodium (60 mg/kg) mixed with heparin (1,000 U). The heart was then attached to and perfused by a Langendorf apparatus via the aorta. The heart was submerged in perfusate while the atria were opened and leaflets of the mitral and tricuspid valves detached. A plastic ring was sutured into the mitral annulus to secure the ventricle to the conduit. The atrioventricular node was surgically ablated. A fluid-filled latex balloon was threaded through the ring and into the LV. A micromanometer-tipped catheter (model SPC-330A, Millar, Houston, TX) within the balloon measured instantaneous LV pressure. The monophasic action potential (MAP) was recorded and monitored in real time from an electrode placed on the LV epicardial surface, away from regionally ischemic regions (model 200, EP Technologies, Sunnyvale, CA). Wire pacing electrodes were placed on the epicardial surface of the LV apex and right ventricle and paced the heart at 2 Hz. The isotonic perfusate consisted of 120 mM NaCl, 5.0 mM KCl, 20 mM sodium acetate, 1.2 mM MgCl2, 5.0 mM HEPES, 1.5 mM CaCl2, 10 mM glucose, 0.3 mM probenecid, and 0.05 mM NaOH. After filtration (0.45 m), 1% neonatal calf serum was added. The solution was bubbled with 100% O2, and the pH was maintained at ⬃7.4. Coronary perfusion pressure (CPP) was maintained between 70 and 80 mmHg throughout the experiment and checked periodically. The volume pump consists of a hydraulic piston driven by a stepper motor apparatus (Compumotor Indexer model AT 6400, microstepping drive model S6, and Linear Motor Platen model PO-L20-P18, Parker Compumotor, Rohnert Park, CA). A resistive linear variable displacement transducer (DRC model LX1A-0004-BE-L10, Parker Compumotor) determined the position of the piston. The output of the linear variable displacement transducer was calibrated to measure absolute balloon volume (linearity within 1%) and was digitized at 1 kHz by a digital computer (model 486-DX4-66, Gateway 2000, North Sioux City, SD) using a 12-bit analog-to-digital converter (LabMaster TM-100, Scientific Solutions, Solon, OH). The MAP, LV pressure, the rate of rise of the LV pressure, LV volume, and coronary perfusion pressure were amplified and continuously digitized during each experimental stage at 1 kHz by the LabMaster TM-100 analog-to-digital board and stored at 500 Hz on the computer’s hard disk for subsequent data analysis. Experimental protocols. Between stretch protocols, isovolumic measurements were taken to monitor ventricular mechanics. The LV stretch protocol (stretch) consisted of 20 iterations of a control-stretch cycle where each cycle was composed of eight pacing beats followed by a quiescent pacing period to exclude intrinsic ectopia. Pacing was then resumed and continued for 4 s (8 beats) before a transient diastolic stretch was delivered by precise increase of the LV balloon volume (⌬V), followed by a return to the initial steady-state volume. During stretch, no pacing signals were delivered to the heart. From the 20 cycles, a probability of ventricular SIA (PSIA) was computed at each ⌬V such that a PSIA vs. ⌬V curve was established at baseline condition (nonischemic). A value from this sigmoidal curve corresponding to a 50% PSIA value was chosen and tested at intervals throughout the experiment. To induce global ischemia (n ⫽ 6), perfusion pressure was reduced from 80 to 40 mmHg. Regional ischemia (n ⫽ 9) was induced by ligation of the left circumflex. Reperfusion of the ischemic region occurred after 30 min of ischemia by release of the ligature. Control, or mock ischemia, experiments (n ⫽ 6) were conducted where a suture was placed around the left circumflex but not tied. Data are reported as means ⫾ SE. Trends in each parameter with time were assessed by one-way ANOVA using Analyse-it 1.70 (Analyse-it Software, Leeds, UK). If the overall trend with time was significant, values of PSIA, maximum systolic pressure (Pmax), and end-diastolic pressure (Ped) were each compared with baseline using Bonferroni’s correction for multiple comparisons. Single comparisons of PSIA, Pmax, and Ped in hearts that were globally or regionally ischemic for 5 min vs. their baseline values were made with Student’s t-test for paired samples. A value of P ⬍ 0.05 was considered significant for all tests. MECHANOARRHYTHMIAS DURING ISCHEMIA AND REPERFUSION 379 Mock ischemic hearts show a gradual, but statistically insignificant, degradation of Pmax during Langendorf perfusion (ANOVA, P ⫽ 0.29). Ped values were unchanged for ischemic (ANOVA, P ⫽ 0.79) and mock ischemic hearts (ANOVA, P ⫽ 0.93). Thus LV compliance was relatively constant throughout our experiments, whereas LV contractility was reduced during ischemia and restored during reperfusion. The mechanoarrhythmogenic effects of ischemia and reperfusion are summarized in Fig. 3B. In the figure, the mean PSIA is plotted as a function of time and the onset and duration of coronary artery occlusion and reperfusion are indicated. A 25% (P ⬍ 0.05) increase in PSIA was observed 5 min after the onset of ischemia. Twenty minutes after the onset of ischemia, PSIA had continued to increase an additional 30% (P ⬍ 0.05) over baseline; however, this time point is at the transitional period when phase Ib arrhythmias are most often observed (21) and cell-to-cell electrical uncoupling begins (49). Previous studies showing disruption of gap junction conductivity during transient ischemia suggest that electrical isolation of the infarct Downloaded from jap.physiology.org on January 5, 2009 Fig. 1. Stretched-induced arrhythmias (SIA). A: stretch-induced ventricular tachycardia. B: stretch-induced ventricular fibrillation. MAP, monophasic action potential; LVV, left ventricular volume; LVP, left ventricular pressure. (49). We induced regional ischemia by coronary artery ligature for 30 min and then released the suture, reperfusing the ischemic region. The hemodynamic effects of acute coronary artery occlusion and reperfusion are shown in Fig. 3. In the figure, time course of the experiment and the changes in diastolic and systolic pressures, as well as the change in PSIA, during ischemia and reperfusion are depicted. In Fig. 3A, the immediate loss of Pmax after coronary artery occlusion is observed, but it is recovered during reperfusion where contractility recovers to levels comparable with mock ischemic hearts. J Appl Physiol • VOL Fig. 2. Global ischemic vs. regional ventricular ischemia. A: maximum systolic pressure (Pmax) and end-diastolic pressure (Ped) during 5 min of acute ischemia. Reg, regional; Isch, ischemia. B: probability of ventricular SIA (PSIA) during acute ischemia. *P ⬍ 0.05. 97 • JULY 2004 • www.jap.org 380 MECHANOARRHYTHMIAS DURING ISCHEMIA AND REPERFUSION Twenty consecutive stretch sequences before ligation of the left circumflex artery, 5 min after ligation, and 5 min into reperfusion are depicted. Single ventricular extrasystoles, ventricular pairs, and nonsustained ventricular tachycardia are observed as the PSIA increases from 0.50 before ischemia, to 0.80 during ischemia, and then to 1.00 during reperfusion. When extrasystoles and ventricular pairs occurred after stretch, they were excluded from consideration because they were probably ventricular escape beats. PSIA remained higher than any value measured during ischemia throughout the observed period of reperfusion (P ⬍ 0.05 at 20 min) even while the value of Pmax is similar to that measured in control experiments where no such increase in PSIA is observed. Thus it would appear that the restoration of contractility within the infarcted region is not sufficient to reduce the risk of SIA. DISCUSSION Fig. 3. Hemodynamic and arrhythmogenic response to acute regional ischemia and reperfusion. A: Pmax and Ped. B: PSIA. would occur at a time ⬎20 min after coronary artery occlusion (49). After 30 min, the mean value of PSIA had fallen to a level that was not statistically significant vs. baseline levels (P ⬎ 0.05). We attribute this decrease to electrical uncoupling of the ischemic region from perfused regions, thus isolating regions within the infarct that might have increased sensitivity to arrhythmogenic stimuli such as stretch. For a SIA to occur, a critical volume of tissue must be depolarized to threshold and a conduction pathway from this tissue must exist. We hypothesize that electrical uncoupling prevents the development of stretch-induced action potentials originating within the infarct. Five minutes after release of the ligature constricting the left circumflex, PSIA increases substantially, exceeding values observed during ischemia, with nearly a 40% increase over preischemic values (P ⬍ 0.05). This occurs at the same time that Pmax returns to values comparable to that of mock ischemic hearts. Thus, even though contractile capability is restored, PSIA increases substantially. The increase in PSIA during the first 5 min of ischemia and after 5 min of reperfusion is illustrated in Fig. 4, which shows typical MAP recordings during an experiment. J Appl Physiol • VOL Fig. 4. Twenty monophasic waveforms recorded during a typical experiment. Recordings were made at baseline (preischemia), after 5 min of regional ischemia (ischemia), and after 5 min of reperfusion (reperfusion). Vertical shaded bars indicate timing of left ventricular volume increase (stretch). 97 • JULY 2004 • www.jap.org Downloaded from jap.physiology.org on January 5, 2009 Regional ischemia facilitates stretch-induced arrhythmias. Our data suggest that arrhythmogenic events potentiated by transient LV dilatation during ischemia are sensitive to the geometry of the ischemic region. Although global ischemia may exacerbate the normal regional differences in diastolic and systolic function, the gradients in electrical and mechanical function are not as locally concentrated as observed during regional ischemia, where such differences may occur with a spatial dispersion on the scale of cell lengths. Ischemic ventricular myocardium has been shown to be less contractile than normal surrounding myocardium (1, 29). Within minutes of acute myocardial ischemia, paradoxical holosystolic lengthening is observed (54). This lengthening is attributed to the reduced rate and magnitude of tension development with respect to noninfarcted regions against which it MECHANOARRHYTHMIAS DURING ISCHEMIA AND REPERFUSION J Appl Physiol • VOL contractile function. Our data suggest that some of the attributes of acute ischemia and reperfusion, including increased cytosolic calcium and hypercontracture associated with reoxygenation of the tissue, contribute to the heart’s increased vulnerability to mechanoarrhythmogenic stimuli. Two factors are credited with facilitating reperfusion arrhythmias: cytosolic calcium overload (34) and oxygen-derived free radicals (4). Both factors may act synergistically (18, 33), or calcium overload alone may facilitate the development of early ventricular arrhythmias (9, 18, 34). Increased levels of cytosolic calcium may increase the responsiveness of myocardial tissue to stretch. However, another potential factor in the increased susceptibility of reperfused hearts to arrhythmia may be the affects of hypercontracture and associated ultrastructural damage. Hypercontracture in nonbeating myocytes is defined as an additional increase in cell shortening on reoxygenation (52). The myofibrillar contraction (5, 64) is preceded by the uncontrolled calcium influx into the reperfused myocytes (47). With reenergization of the tissue, there is hyperactivation of contractile elements within the cell and hypercontracture (37, 59). In the tissue microenvironment, this leads to membrane disruption and cell death as a result of intracellular force transmission (16). The increased internal stresses within the cytoskeleton of a hypercontracted cell are likely to alter the kinetics of those channels that are modulated by cytoskeletal protein interactions (55). Also, selective degradation of cytoskeletal-associated proteins such as myosin light chain-1 has been shown to occur during reperfusion but not during ischemia (57). These combined effects may render ventricular myocytes highly vulnerable to arrhythmogenic mechanoelectrical coupling during reperfusion. In conclusion, the results of this study indicate that regionally ischemic hearts are more susceptible to ventricular SIAs during time periods corresponding to phase Ia ischemia, suggesting a possible mechanism for the genesis of the triggered arrhythmias during this period. This study also indicates that mechanoelectrical coupling may contribute to the triggered ventricular arrhythmias during reperfusion after acute ischemia. The latter result suggests that preventative measures against arrhythmogenic mechanoelectric signaling may be beneficial during the administration of thrombolytic therapies. GRANTS This project was funded by National Heart, Lung, and Blood Institute Grants HL-46681 (D. E. Hansen) and 5T32-HL-07411 (Predoctoral Fellowship in Cardiology, Institutional Training Grant to K. K. Parker). J. A. Lavelle was the Dan May Summer Scholar and Benjamin F. Byrd Scholar from the American Heart Association, Tennessee Affiliate. REFERENCES 1. Allen DG and Orchard CH. Myocardial contractile function during ischemia and hypoxia. Circ Res 60: 152–168, 1987. 2. Barrett TD, MacLeod BA, and Walker MJA. A model of myocardial ischemia for the simultaneous assessment of electrophysiological changes and arrhythmias in intact rabbits. J Pharmacol Toxicol Methods 37: 27–36, 1997. 3. Bellemin-Baurreau J, Poizot A, Hicks PE, and Armstrong MJ. An in vitro method for the evaluation of antiarrhythmic and antiischemic agents by using programmed electrical stimulation of the rabbit heart. J Pharmacol Toxicol Methods 31: 31– 40, 1994. 4. Bernier M, Hearse DJ, and Manning AS. Reperfusion-induced arrhythmias and oxygen-derived free radicals. Studies with ’anti-free radical’ interventions and a free radical-generating system in the isolated perfused rat heart. Circ Res 58: 331–340, 1986. 97 • JULY 2004 • www.jap.org Downloaded from jap.physiology.org on January 5, 2009 contracts. Experimental preparations of weak and strong myocardial tissue in series demonstrate paradoxical lengthening of weaker regions (61). This has also been demonstrated by segment length measurements during regional ischemia of intact hearts (27). Previously, the contractile and restitutive heterogeneity induced by regional ischemia was shown to alter ventricular wall mechanics and has been correlated with the incidence of arrhythmias (6, 8, 31, 62) and sudden cardiac death (7, 48, 53, 60). In patients diagnosed with LV infarcts, regions of anomalous deformation were noted during magnetic resonance imaging tagging studies (28) and were attributed to stretch. An early report also noted asynchronous contraction and relaxation of ischemic regions compared with well-perfused, surrounding myocardium (56). These reports support the conclusion that inhomogeneities in activation and contractility, such as those induced by ischemia, may contribute to the development of stretch-induced arrhythmogenic foci. Although the above-mentioned studies refer to systolic stretch, the regional heterogeneities induced by acute ischemia will also affect diastolic distensibility (26). Theoretical calculations (25, 45) predict eccentric strain patterns in the ischemic border region and in outlying regions of the infarct during diastolic filling that are not present during global ischemia. The spatial patterning of strain was reported to be similar during both systole and transient diastolic stretch. These regions of eccentric strain may serve as foci for mechanoarrhythmogenic events. These reports focus on the inhomogeneity presented by localized ischemia, and others have focused on the regional inhomogeneities presented by dilatation (11). However, should localized regions of hypertrophy or scarring be present in the intact ventricle, the hypothesis may extend to the mechanical abnormalities that these conditions present as well. Mechanoelectrical coupling potentiates phase Ia arrhythmias. The results of this study indicate that regionally ischemic hearts are more vulnerable to ventricular SIAs during the time period associated with phase Ia arrhythmias than that period corresponding to phase Ib arrhythmias. Previous reports in the literature foreshadow this finding because Ia arrhythmias have been correlated to both reentrant and triggered mechanisms (39, 40), whereas Ib arrhythmias are correlated exclusively to reentrant means (38). The inability to mechanically induce arrhythmias above baseline during phase Ib implies that, at a certain point during acute ischemia, vulnerability to arrhythmogenic mechanoelectrical coupling is reduced. Disruption of gap junctions after ⬎20 min of ischemia serves to electrically uncouple ischemic and perfused regions of the heart (49). Our choice of the rabbit as an experimental model was due in part to their lack of coronary collaterals (2, 3, 30). Thus a relatively strict demarcation of the ischemic region is achieved after gap junction closure. Before the present study, we confirmed this in our Langendorf-perfused rabbit heart preparation during optical imaging studies with voltage-sensitive dyes. Thus, when the infarct is electrically isolated, the continuing loss of ionic homeostasis and ultrastructural integrity is prevented from contributing to triggered action potentials propagating from within the ischemic region. Mechanoelectrical coupling potentiates reperfusion-induced arrhythmias. On release of the coronary artery blockade, we observed a rapid increase in the PSIA to levels superseding what was observed in the earliest moments of ischemia. This increase in arrhythmias was accompanied by a restoration of 381 382 MECHANOARRHYTHMIAS DURING ISCHEMIA AND REPERFUSION J Appl Physiol • VOL 29. Marban E and Kusuoka H. Maximal Ca2⫹ activated force and myofilament Ca2⫹ sensitivity in intact mammalian hearts. J Gen Physiol 90: 609 – 623, 1987. 30. Maxwell MP, Hearse DJ, and Yellon DM. Species variation in the coronary collateral circulation during regional myocardial ischaemia: a critical determinant of the rate of evolution and extent of myocardial infarction. Cardiovasc Res 21: 737–746, 1987. 31. Meizlish JL, Berger HJ, Plankey M, Errico D, Levy W, and Zaref BL. Functional left ventricular aneurysm formation after acute anterior transmural myocardial infarction. Incidence, natural history, and prognostic implications. N Engl J Med 311: 1001–1006, 1984. 32. Meuse AJ, Perreault CL, and Morgan JP. Pathophysiology of cardiac hypertrophy and failure of human working myocardium: abnormalities in calcium handling. Basic Res Cardiol 87, Suppl 1: 223–233, 1992. 33. Opie LH. Reperfusion injury and its pharmacologic modification. Circulation 80: 1049 –1092, 1989. 34. Opie LH and Coetzee WA. Role of calcium ions in reperfusion arrhythmias. Relevance to pharmacological intervention. Cardiovasc Drugs Ther 2: 623– 636, 1988. 35. Parker KK, Taylor LK, Atkinson B, Hansen DE, and Wikswo JP. The effects of tubulin-binding agents on stretch–induced ventricular arrhythmias. Eur J Pharmacol 417: 131–140, 2001. 36. Penefsky ZJ and Hoffman BF. Effects of stretch on mechanical and electrical properties of cardiac muscle. Am J Physiol 204: 433– 438, 1963. 37. Piper HM, Siegmund B, and Schluter KD. Prevention of the oxygen paradox in the isolated cardiomyocyte and the whole heart. Am J Cardiovasc Pathol 88: 471– 482, 1993. 38. Pogwizd SM and Corr PB. Electrophysiologic mechanisms underlying arrhythmias due to reperfusion of ischemic myocardium. Circulation 76: 404 – 426, 1987. 39. Pogwizd SM and Corr PB. Reentrant and nonreentrant mechanisms contribute to arrhythmogenesis during early myocardial ischemia: results using three-dimensional mapping. Circ Res 61: 352–371, 1987. 40. Pogwizd SM and Corr PB. Mechanisms underlying the development of ventricular fibrillation during early myocardial ischemia. Circ Res 66: 672– 695, 1990. 41. Reiter MJ. Effects of mechano-electrical feedback: potential arrhythmogenic influence in patients with congestive heart failure. Cardiovasc Res 32: 44 –51, 1996. 42. Rice JJ, Winslow RL, Dekanski J, and McVeigh E. Model studies of the role of mechano-sensitive currents in the generation of cardiac arrhythmias. J Theor Biol 190: 295–312, 1998. 43. Riemer TL, Sobie EA, and Tung L. Stretch-induced changes in arrhythmogenesis and excitability in experimentally based heart cell models. Am J Physiol Heart Circ Physiol 275: H431–H442, 1998. 44. Roelandt P, Klootwijk J, Lubsen J, and Janse MJ. Sudden death during long-term ambulatory monitoring. Eur Heart J 5: 7–20, 1984. 45. Roth BJ and Parker KK. Stretch around an inhomogeneity in cardiac tissue (Abstract). Ann Biomed Eng 48: S-82, 1998. 46. Shaw RM and Rudy Y. Electrophysiologic effects of acute myocardial ischemia. Circ Res 80: 124 –138, 1997. 47. Shen AJ and Jennings RB. Kinetics of calcium accumulation in acute myocardial ischemia injury. Am J Pathol 67: 441– 452, 1972. 48. Shultz RA, Strauss HW, and Pitt B. Sudden death in the year following myocardial infarction. Am J Med 62: 192–199, 1977. 49. Smith WT, Fleet WF, Johnson TA, Engle CL, and Cascio WE. The Ib phase of ventricular arrhythmias in ischemic in situ porcine heart is related to changes in cell-to-cell electrical coupling. Circulation 92: 3051–3060, 1995. 50. Sra J, Dhala A, Blanck Z, Deshpande S, Cooley R, and Akhtar M. Sudden cardiac death. Curr Probl Cardiol 24: 461–540, 1999. 51. Stacy GP Jr, Jobe RL, Taylor LK, and Hansen DE. Stretch-induced depolarizations as a trigger of arrhythmias in isolated canine left ventricles. Am J Physiol Heart Circ Physiol 263: H613–H621, 1992. 52. Stowe DF. Understanding the temporal relationship of ATP loss calcium loading and rigor contracture during anoxia, and hypercontracture after anoxia in cardiac myocytes. Cardiovasc Res 43: 285–287, 1999. 53. Taggart P. Mechano-electric feedback in the human heart. Cardiovasc Res 32: 38 – 43, 1996. 54. Tennant R and Wiggers CJ. The effect of coronary occlusion on myocardial contraction. Am J Physiol 112: 351–361, 1996. 55. Terzic A and Kurachi Y. Cytoskeleton effects on ion channels. In: Cell Physiology Source Book (2nd ed.), edited by Sperelakis N. New York: Academic, 1998, p. 532–546. 97 • JULY 2004 • www.jap.org Downloaded from jap.physiology.org on January 5, 2009 5. Bullock GR. Structural changes at cardiac cell functions during ischemia. J Mol Cell Cardiol 18, Suppl 4: 1–5, 1986. 6. Califf RM, Burks JM, Behar VS, Margolis JR, and Wagner GS. Relationships among ventricular arrhythmias, coronary artery disease, and angiographic and electrocardiographic indicators of myocardial fibrosis. Circulation 57: 725–731, 1978. 7. Califf RM, McKinnis RA, and Burks J. Prognostic implications of ventricular arrhythmias during 24 h ambulatory monitoring in patients undergoing cardiac catherization for coronary artery disease. Am J Cardiol 50: 23–31, 1982. 8. Calvert A, Lown B, and Gorlin R. Ventricular premature beats in anatomically defined heart disease. Am J Cardiol 39: 627– 634, 1977. 9. Coetzee WA, Owen P, Dennis SC, Saman S, and Opie LH. Reperfusion damage: free radicals mediate delayed membrane changes rather than early ventricular arrhythmias. Cardiovasc Res 24: 156 –164, 1990. 10. Davies MJ. Anatomic features in victims of sudden coronary death: coronary artery pathology. Circulation 85, Suppl I: I19 –I24, 1992. 11. Dong SJ, MacGregor JH, Crawley AP, McVeigh E, Belenkie I, Smith ER, Tyberg JV, and Beyar R. Left ventricular wall thickness and regional systolic function in patients with hypertrophic cardiomyopathy. Circulation 90: 1200 –1209, 1994. 12. Feild BJ, Russell RO, Dowling JT, and Rackley CE. Regional left ventricular performance in the year following myocardial infarction. Circulation 46: 479 – 689, 1972. 13. Franz MR, Burkhoff D, Yue DT, and Sagawa K. Mechanically induced action potential changes and arrhythmia in isolated and in situ canine hearts. Cardiovasc Res 23: 213–223, 1989. 14. Franz MR, Cima R, Wang D, Profitt D, and Kurz R. Electrophysiological effects of myocardial stretch and mechanical determinants of stretch-activated arrhythmias. Circulation 86: 968 –978, 1992. 15. Galli A and DeFelice LJ. Inactivation of L-type Ca channels in embryonic chick ventricle cells: dependence on the cytoskeletal agents colchicine and taxol. Biophys J 67: 2296 –2304, 1994. 16. Ganote CE. Contraction band necrosis and irreversible myocardial injury. J Mol Cell Cardiol 15: 67–73, 1983. 17. Hansen DE, Craig SC, and Hondeghem LM. Stretch-induced arrhythmias in the isolated canine ventricle: evidence for the importance of mechanoelectrical feedback. Circulation 81: 1094 –1105, 1990. 18. Hearse DJ and Tosaki A. Free radicals and calcium: simultaneous interacting triggers as determinants of vulnerability to reperfusion-arrhythmias in the rat heart. J Mol Cell Cardiol 20: 213–223, 1988. 19. Hennekes R, Kaufmann R, and Lab M. The dependence of cardiac membrane excitation and contractile ability on active muscle shortening (cat papillary muscle). Pflügers Arch 392: 22–28, 1981. 20. Hennekes R, Kaufmann R, Lab M, and Steiner R. Feedback loops involved in cardiac excitation-contraction coupling: evidence for two different pathways. J Mol Cell Cardiol 9: 699 –713, 1977. 21. Kaplinsky E, Ogawa S, Balke W, and Dreifus LS. Two periods of early ventricular arrhythmia in the canine acute myocardial infarction model. Circulation 60: 397– 403, 1979. 22. Kaufmann R, Lab MJ, Hennekes R, and Kraus H. Feedback interaction of mechanical and electrical events in the isolated ventricular myocardium (cat papillary muscle). Pflügers Arch 332: 96 –116, 1971. 23. Kleber AG, Fleischhauer J, and Cascio WE. Ischemia-induced propagation failure in the heart. In Cardiac Electrophysiology: From Cell to Bedside, edited by Zipes DP and Jalife J. Philadelphia, PA: Saunders, 1995, p. 174 –182. 24. Lab MJ. Mechanically dependant changes in action potentials recorded from the intact frog ventricle. Circ Res 42: 519 –529, 1978. 25. Latimer DC, Roth BJ, and Parker KK. Analytical model for predicting mechanotransduction effects in engineered cardiac tissue. Tissue Eng 9: 283–289, 2003. 26. Lew WYW. Functional consequences of regional heterogeneity in the left ventricle. In: Theory of Heart, edited by Glass L, Hunter P, and McCulloch A. New York: Springer-Verlag, 1991, p. 561–581. 27. Lew WYW, Chen Z, Guth B, and Covell JW. Mechanisms of augmented segment shortening in nonischemic areas during acute ischemia of the canine left ventricle. Circ Res 56: 351–358, 1985. 28. Lugo-Olivera CH, Moore CC, Poon EGC, Lima JAC, McVeigh ER, and Zerhouni EA. Temporal evolution of the three dimensional deformation in the ischemic human left ventricle: assessment by MR tagging. Mtg Soc Magn Reson 2nd San Francisco 1994. MECHANOARRHYTHMIAS DURING ISCHEMIA AND REPERFUSION 56. Tyberg JV, Forrester JS, and Parmley WW. Altered segmental function and compliance in acute myocardial ischemia. Eur J Cardiol 1: 307–317, 1974. 57. Van Eyk JE, Powers F, Law W, Larue C, Hodges RS, and Solaro RJ. Breakdown and release of myofilament proteins during ischemia and ischemia/reperfusion in rat hearts. Circ Res 82: 261–271, 1998. 58. Van Wagoner DR. Mechanosensitive gating of atrial ATP-sensitive potassium channels. Circ Res 72: 973–983, 1993. 59. Vander Heide RS, Angelo JP, Altschuld RA, and Ganote CE. Energy dependence of contraction band formation in perfused hearts and isolated adult myocytes. Am J Pathol 125: 55– 68, 1986. 60. Weaver WD, Lorch GS, Alvarez HA, and Cobb LA. Angiographic findings and prognostic indicators in patients resuscitated from cardiac death. Circulation 54: 895–900, 1976. 383 61. Weigner AW, Allen GJ, and Bing OHL. Weak and strong myocardium in series: implications for segmental dysfunction. Am J Physiol Heart Circ Physiol 235: H776 –H783, 1978. 62. White HD, Norris RN, Brown MA, Brandt PW, Whitlock RML, and Wild CJ. Left ventricular end systolic volume as the major determinant of survival after recovery from myocardial infarction. Circulation 76: 44 –51, 1987. 63. Wit AL and Janse MJ. The Ventricular Arrhythmias of Ischemia and Infarction: Electrophysiological Mechanisms. New York: Futura, 1992, p. 648. 64. Zimmerman A, Daems W, Husmann WC, Snider J, Wisse E, and Durrer D. Morphologic changes of heart muscle caused by successive perfusion with calcium-free and calcium-containing solutions (calcium paradox). Cardiovasc Res 1: 201–209, 1967. Downloaded from jap.physiology.org on January 5, 2009 J Appl Physiol • VOL 97 • JULY 2004 • www.jap.org